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WO2022052926A1 - Composé d'éthylène aromatique et son procédé de préparation, intermédiaire, composition pharmaceutique et utilisation associés - Google Patents

Composé d'éthylène aromatique et son procédé de préparation, intermédiaire, composition pharmaceutique et utilisation associés Download PDF

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Publication number
WO2022052926A1
WO2022052926A1 PCT/CN2021/117066 CN2021117066W WO2022052926A1 WO 2022052926 A1 WO2022052926 A1 WO 2022052926A1 CN 2021117066 W CN2021117066 W CN 2021117066W WO 2022052926 A1 WO2022052926 A1 WO 2022052926A1
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Prior art keywords
alkyl
substituted
alkoxy
independently
compound
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Chinese (zh)
Inventor
王玉光
张农
吴添智
何敏
吴新亮
张顺利
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Guangzhou Maxinovel Pharmaceuticals Co Ltd
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Guangzhou Maxinovel Pharmaceuticals Co Ltd
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Priority claimed from CN202110995765.3A external-priority patent/CN114230512B/zh
Application filed by Guangzhou Maxinovel Pharmaceuticals Co Ltd filed Critical Guangzhou Maxinovel Pharmaceuticals Co Ltd
Priority to JP2023515809A priority Critical patent/JP2023540612A/ja
Priority to US18/042,599 priority patent/US20230331675A1/en
Priority to EP21865980.3A priority patent/EP4212511A4/fr
Publication of WO2022052926A1 publication Critical patent/WO2022052926A1/fr
Anticipated expiration legal-status Critical
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C229/18—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
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    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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    • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to an aromatic vinyl compound, its preparation method, intermediate, pharmaceutical composition and application thereof.
  • PD-1 programmed death 1
  • programmed death receptor 1 is an important immunosuppressive molecule. It is a member of the CD28 superfamily and was originally cloned from the apoptotic mouse T cell hybridoma 2B4.11. Immunomodulation targeting PD-1 is of great significance in anti-tumor, anti-infection, anti-autoimmune diseases and organ transplantation survival. Its ligand PD-L1 can also be used as a target, and the corresponding antibody can also play the same role.
  • PD-1/PD-L1 plays a negative immunoregulatory role.
  • PD-1 on the cell surface is coupled to PD-L1, it can lead to Tyr phosphorylation of the immunoreceptor tyrosine-based switch motif (ITSM) domain in the cytoplasmic region of T cells, and then Phosphorylated Tyr recruits the phosphatases protein tyrosinase 2 and protein tyrosinase 1, which block not only the activation of extracellular signal-regulated kinases, but also phosphatidylinositol 3-kinase (PI3K) and Activation of serine-threonine protein kinase (Akt) ultimately inhibits T lymphocyte proliferation and the secretion of related cytokines.
  • IRS immunoreceptor tyrosine-based switch motif
  • PD-1/PD-L1 signaling inhibits T cell activation and proliferation, and at the same time, the secretion of cytokines interleukin 2 (IL2), interferon gamma and IL-10 is also reduced (Eur.J.Immunol., 2002 , 32(3), 634-643.).
  • IL2 interleukin 2
  • IL-10 interferon gamma
  • PD-1/PD-L1 signaling is also similar to T cells in the immune function of B cells.
  • the cytoplasmic region of PD-1 binds with protein tyrosinase 2
  • the tyrosinase at the site acts to ultimately block the activation of B cells.
  • PD-1/PD-L1 The role of immunonegative regulator PD-1/PD-L1 in tumor immune escape has attracted more and more attention.
  • a large number of studies have confirmed that PD-L1 on the surface of tumor cells in the tumor microenvironment is increased, and at the same time, it binds to PD-1 on activated T cells and transmits negative regulatory signals, resulting in tumor antigen-specific T cells apoptosis or immune incompetence. This inhibits the immune response, which in turn promotes the escape of tumor cells.
  • PD-1/PD-L1 antibody inhibitors include BMS's Nivolumab (2014), Merck's Lambrolizumab (2014) and Roche's Atezolizumab (2016).
  • the PD-1/PD-L1 antibody inhibitors under development include Cure Tech's Pidilizumab, GSK's AMP-224 and AstraZeneca's MEDI-4736.
  • the above are all biological macromolecules, while small molecule PD-1/PD-L1 inhibitors are still in the early stage of development.
  • WO2015044900 has just entered clinical phase I, and the small molecule PD-1/PD-L1 inhibitors of BMS benzyl phenyl ethers (WO2015034820, WO2015160641, WO2017066227, WO2018009505, WO2018044963, WO2018118848) are still in the preclinical research stage, and Incyte is also doing a series of small molecule PD-1 / PD-L1 inhibitor (WO2017070089, WO2017087777, WO2017106634, WO2017112730, WO2017192961, WO2017205464, WO2017222976, WO2018013789, WO2018044783, WO2018119221, WO2018119224, WO2018119263, WO2018219266, WO2018119286) still in preclinical studies .
  • small molecule compounds can cross the cell membrane and act on intracellular targets, so they have a wide range of applications.
  • chemically modified small molecules often have good bioavailability and compliance, effectively avoiding the decomposition and inactivation of enzymes in the digestive tract.
  • the research on small molecules is also quite mature in various aspects such as production process, dosage form design and administration method.
  • the technical problem solved by the present invention is to provide a vinyl aromatic compound completely different from the prior art, its preparation method, intermediate, pharmaceutical composition and application thereof.
  • the aromatic vinyl compound of the present invention has obvious inhibitory effect on PD-1/PD-L1, and at the same time has higher peak drug concentration, larger area under the drug-time curve and better oral bioavailability, and is a class of PD-1/PD-L1 is a very effective small molecule inhibitor, which can effectively alleviate or treat related diseases such as cancer.
  • the present invention provides an aromatic vinyl compound represented by formula I-0, its tautomer, its stereoisomer, its racemate or its isotopic derivative, or their (referring to the aforementioned formula A pharmaceutically acceptable salt of a vinyl aromatic compound represented by I-0, its tautomer, its stereoisomer, its racemate or its isotopic derivative);
  • R 1 is cyano, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more deuterium, halogen, C 1 -C 4 alkyl substituted with one or more halogen;
  • R 3 , R 6 , R 12 , R 13 and R 14 are independently H or deuterium;
  • R 2 is hydroxy, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more RA -1 , C 1 -C 6 alkoxy, or substituted with one or more RA -2- substituted C 1 -C 6 alkoxy;
  • R 4 and R 5 are independently hydroxy, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more R B-1 , C 1 -C 6 alkoxy, or C 1 -C 6 alkoxy or substituted by one or multiple R B-2 substituted C 1 -C 6 alkoxy groups;
  • R B-1 and R B-2 are independently deuterium, hydroxy, halogen, cyano, C 6 -C 10 aryl, C 6 -C 10 aryl substituted with one or more R B-1-3 , 3-12 membered heteroaryl, 3-12 membered heteroaryl substituted with one or more R B-1-4 , C 1 -C 4 alkoxy, C 1 -C substituted with one or more deuterium 4 alkoxy,
  • the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4;
  • R B-1-3 and R B-1-4 are independently cyano, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
  • R B-1-1 and R B-1-2 are independently H, deuterium, C 1 -C 4 alkyl, or C 1 -C 4 alkyl substituted with one or more R B-1-1-1 , the R B-1-1-1 is deuterium, hydroxyl or COOR B-1-1-5 ;
  • R B-1-1 , R B-1-2 and the nitrogen atom to which they are attached together form a 5-7 membered carboheterocycle or a carboheterocycle substituted with one or more R B-1-1-2 ring, in the carbon heterocycle, the heteroatom is selected from one or more of N, O and S, the number of heteroatoms is 1-4, and the R B-1-1-2 is deuterium, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more deuterium, COOR B - 1-1-6 or C 1 -C 4 amido;
  • R A-1-1-2 , R B-1-1-5 and R B-1-1-6 are independently H, deuterium, C 1 -C 4 alkyl or C substituted with one or more deuterium 1 -C 4 alkyl;
  • R 7 , R 8 , R 9 , R 10 and R 11 are independently H or deuterium;
  • R 15 and R 16 are independently H, deuterium or halogen.
  • R B-1 and R B-2 are independently deuterium, hydroxyl, halogen, cyano, C 1 -C 4 alkane oxy, C 1 -C 4 alkoxy substituted with one or more deuterium, Other variables are defined as described in any aspect of the present invention.
  • the present invention provides an aromatic vinyl compound shown in formula I, its tautomer, its stereoisomer, its racemate or its isotopic derivative, or them (referring to the aforementioned formula I as shown in the formula I)
  • R 1 is cyano, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more deuterium;
  • R 3 , R 6 , R 12 , R 13 and R 14 are independently H or deuterium;
  • R 2 is hydroxy, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more RA -1 , C 1 -C 6 alkoxy, or substituted with one or more RA -2- substituted C 1 -C 6 alkoxy;
  • R 4 and R 5 are independently hydroxy, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more R B-1 , C 1 -C 6 alkoxy, or C 1 -C 6 alkoxy or substituted by one or multiple R B-2 substituted C 1 -C 6 alkoxy groups;
  • R B-1 and R B-2 are independently deuterium, hydroxy, halogen, cyano, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy substituted with one or more deuterium,
  • R B-1-1 and R B-1-2 are independently H, deuterium, C 1 -C 4 alkyl, or C 1 -C 4 alkyl substituted with one or more R B-1-1-1 , the R B-1-1-1 is deuterium, hydroxyl or COOR B-1-1-5 ;
  • R B-1-1 , R B-1-2 and the nitrogen atom to which they are attached together form a 5-7 membered carboheterocycle or a carboheterocycle substituted with one or more R B-1-1-2 ring, in the carbon heterocycle, the heteroatom is selected from one or more of N, O and S, the number of heteroatoms is 1-4, and the R B-1-1-2 is deuterium, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more deuterium, COOR B - 1-1-6 or C 1 -C 4 amido;
  • R A-1-1-2 , R B-1-1-5 and R B-1-1-6 are independently H, deuterium, C 1 -C 4 alkyl or C substituted with one or more deuterium 1 -C 4 alkyl;
  • R 7 , R 8 , R 9 , R 10 and R 11 are independently H or deuterium.
  • the C 1 -C 4 alkyl group is a methyl group , ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, eg methyl, and other variables are as defined in any of the embodiments of the present invention.
  • the C 1 -C 4 alkyl substituted with one or more deuteriums is C 1 -C 2 alkyl substituted with one or more deuteriums, for example, deuteromethyl, di-deuteromethyl, tri-deuteromethyl, mono-deuteroethyl , di-deuteroethyl, tri-deuteroethyl, tetra-deuteroethyl or penta-deuteroethyl, another example is tri-deuteromethyl, and the definitions of other variables are as described in any scheme of the present invention.
  • the halogen is fluorine, chlorine, bromine or iodine, such as chlorine, and other variables of The definitions are as described in any of the embodiments of the present invention.
  • the halogen is Fluorine, chlorine, bromine or iodine, eg fluorine, and other variables are as defined in any of the embodiments of the present invention.
  • the C 1 -C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, eg methyl, other variables are as defined in any of the embodiments of the present invention.
  • the halogen is fluorine, chlorine, bromine or iodine, such as chlorine, and other variables of The definitions are as described in any of the embodiments of the present invention.
  • the C 1 -C 4 alkyl group is a methyl group , ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, eg methyl, and other variables are as defined in any of the embodiments of the present invention.
  • the Said C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl, and the definitions of other variables are as in any scheme of the present invention said.
  • each The R A-1s are the same or different, and the multiple is 2, 3, 4 or 5, and the definitions of other variables are as described in any scheme of the present invention.
  • the C 1 -C 6 alkoxy is C 1 -C 4 alkoxy, such as methoxy, ethoxy, n-propoxy or n-butoxy, again for example methoxy, and other variables are as defined in any of the embodiments of the present invention.
  • the vinyl aromatic compound represented by formula I-0 or I when R 2 is C 1 -C 6 alkoxy substituted by one or more R A-2 ,
  • the C 1 -C 6 alkoxy group is a C 1 -C 4 alkoxy group, such as methoxy, ethoxy, n-propoxy or n-butoxy, and other variables are defined as in any scheme of the present invention said.
  • R 2 is C 1 -C 6 alkoxy substituted by one or more R A-2
  • R A-2 is the same or different, the multiple is 2, 3, 4 or 5, and the definitions of other variables are as described in any one of the schemes of the present invention.
  • the halogen is fluorine, chlorine, bromine or iodine, such as fluorine, other variables are as defined in any of the embodiments of the present invention.
  • the C 1 -C 4 alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy, eg methoxy, other variables are as defined in any of the embodiments of the present invention.
  • the C 1 -C 4 alkoxy substituted by one or more deuteriums is a C 1 -C 2 alkoxy substituted by one or more deuteriums, such as a deuteromethoxy, di- Deuteriomethoxy, trideuteriomethoxy, monodeuterioethoxy, dideuteroethoxy, trideuteroethoxy, tetradeuteroethoxy or pentadeuteroethoxy, e.g. trideuteriomethoxy, other variables
  • the definition of is as described in any aspect of the present invention.
  • the C 1 -C 4 alkane are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, eg methyl, and the other variables are as defined in any of the embodiments of the present invention.
  • the C 1 -C 4 alkyl group substituted by one or more deuteriums is the C 1 -C 2 alkyl group substituted by one or more deuteriums, such as deuteromethyl, dideuteromethyl, trideuteromethyl, Mono-deuteroethyl, di-deuteroethyl, tri-deuteroethyl, tetra-deuteroethyl or penta-deuteroethyl, another example is tri-deuteromethyl, and the definitions of other variables are as described in any one of the schemes of the present invention.
  • the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl, ethyl or isopropyl, other variables
  • the definition of is as described in any aspect of the present invention.
  • the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl groups, such as methyl, ethyl or isopropyl, and other variables are as defined in any of the embodiments of the present invention.
  • each R A-1-1-1 is the same or different, the plurality is 2, 3, 4 or 5, the other variables
  • the definitions are as described in any of the embodiments of the present invention.
  • the halogen is fluorine, chlorine, bromine or iodine, for example Chlorine and other variables are as defined in any of the embodiments of the present invention.
  • the C 1 -C 4 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, eg methyl, and other variables are as defined in any of the embodiments of the present invention.
  • the vinyl aromatic compound represented by formula I-0 or I when R 4 and R 5 are independently C 1 -C 4 substituted by one or more R B-1
  • the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl, and other variables are as defined herein Invention as described in any aspect of the invention.
  • R 4 and R 5 are independently C 1 -C 4 substituted by one or more R B-1
  • each R B-1 is the same or different, the multiple is 2, 3, 4 or 5, and the definitions of other variables are as described in any one of the embodiments of the present invention.
  • the C 1 -C 6 alkoxy is C 1 -C 4 alkoxy, such as methoxy, ethoxy, n-propoxy or n-butoxy, and then for example methoxy, other variables are defined as in any scheme of the present invention said.
  • the C 1 -C 6 alkoxy group is a C 1 -C 4 alkoxy group, such as methoxy, ethoxy, n-propoxy or n-butoxy, and the definitions of other variables are as follows Invention as described in any aspect of the invention.
  • each R B-2 is the same or different, the plurality of R B-2 is 2, 3, 4 or 5, and the definitions of other variables are as described in any embodiment of the present invention.
  • the halogen is fluorine, chlorine, Bromine or iodine, eg fluorine, and other variables are as defined in any of the embodiments of the present invention.
  • each R B-1-3 is the same or different, and the multiple is 2, 3, 4 or 5, and the definitions of other variables are as in any scheme of the present invention described in.
  • the A 3-12 membered heteroaryl group is a 5-7 membered heteroaryl group, and the definitions of other variables are as described in any one of the schemes of the present invention.
  • R B-1 and R B - 2 are independently 3-12-membered heteroaryl groups
  • the The heteroatom of the 3-12-membered heteroaryl group is selected from N, the number of heteroatoms is 1, and the definitions of other variables are as described in any scheme of the present invention.
  • the aromatic vinyl compound represented by formula I-0 or I when R B-1 and R B - 2 are independently one or more R B-1-4
  • the 3-12-membered heteroaryl group is a 5-7-membered heteroaryl group, and the definitions of other variables are as described in any scheme of the present invention.
  • R B-1 and R B - 2 are independently one or more R B-1-4
  • the heteroatom of the 3-12-membered heteroaryl group is selected from N, the number of heteroatoms is 1, and the definitions of other variables are as described in any scheme of the present invention.
  • each R B-1-4 is the same or different, and the plurality is 2, 3, 4 or 5, and the definitions of other variables are as in any scheme of the present invention described in.
  • the halogen is fluorine, Chlorine, bromine or iodine, such as fluorine or iodine, and other variables are as defined in any of the embodiments of the present invention.
  • the C 1 -C 4 alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy, eg methoxy, other variables are as defined in any of the embodiments of the present invention.
  • the C 1 -C 4 alkoxy substituted by one or more deuteriums is a C 1 -C 2 alkoxy substituted by one or more deuteriums, such as a deuteromethoxy, Di-deuteriomethoxy, tri-deuteromethoxy, mono-deuteroethoxy, di-deuteroethoxy, tri-deuteroethoxy, tetra-deuteroethoxy or penta-deuteroethoxy, for example tri-deuteromethoxy, others Variables are defined as described in any aspect of the invention.
  • the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl, ethyl or isopropyl, other variables
  • the definition of is as described in any aspect of the present invention.
  • R B-1-1 and R B- 1-2 are independently composed of one or more R B-
  • the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl groups, such as methyl, ethyl or isopropyl, and other variables are as defined in any of the embodiments of the present invention.
  • R B-1-1 and R B- 1-2 are independently composed of one or more R B-
  • each R B-1-1-1 is the same or different, the plurality is 2, 3, 4 or 5, the other variables
  • the definitions are as described in any of the embodiments of the present invention.
  • each R B-1-1-2 is the same or different, and the multiple is 2, 3, 4 or 5, other Variables are defined as described in any aspect of the invention.
  • the C 1 -C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, eg methyl, other variables are as defined in any of the embodiments of the present invention.
  • the R B-1-1-2 is C 1 -C 4 substituted by one or more deuteriums
  • the C 1 -C 4 alkyl group substituted with one or more deuteriums is a C 1 -C 2 alkyl group substituted with one or more deuteriums, such as deuteromethyl, di-deuteromethyl, tri- Deuteromethyl, mono-deuteroethyl, di-deuteroethyl, tri-deuteroethyl, tetra-deuteroethyl or penta-deuteroethyl, another example is tri-deuteromethyl, and the definitions of other variables are as described in any one of the schemes of the present invention.
  • the C 1 -C 4 amide group is R B-1-1-3 and R B-1-1-4 are independently H, deuterium, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with one or more deuteriums, said C 1 -C 4 alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, said C 1 -C 4 substituted by one or more deuteriums Alkyl is, for example, trideuteromethyl, and other variables are as defined in any of the embodiments of the present invention.
  • the aromatic vinyl compound represented by formula I-0 or I when R A-1-1-2 , R B - 1-1-5 and R B-1-1
  • the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl,
  • methyl other variables are as defined in any of the embodiments of the present invention.
  • the halogen is fluorine, chlorine, bromine or iodine, such as fluorine or Bromine, other variables are as defined in any of the embodiments of the present invention.
  • R 3 , R 6 , R 12 , R 13 and R 14 are independently H, and other variables are as defined herein Invention as described in any aspect of the invention.
  • R 2 is halogen, C 1 -C 4 alkyl or C substituted by one or more R A-1 1 - C4 alkyl, other variables are as defined in any of the embodiments of the present invention.
  • R A-1 and R A-2 are independently hydroxyl, halogen, cyano, C 1 -C 4 alkane Oxygen, Other variables are defined as described in any aspect of the present invention.
  • R A-1 is halogen or Other variables are defined as described in any aspect of the present invention.
  • R A-1 is halogen, and the definitions of other variables are as described in any one of the embodiments of the present invention.
  • R A-1-1 is a C 1 -C 4 alkyl group, and the definitions of other variables are as in any scheme of the present invention described in.
  • R A-1-2 and R A- 1-3 are independently H or by one or more R A -1-1-1 substituted C 1 -C 4 alkyl, other variables are defined as described in any one of the schemes of the present invention.
  • one of R A-1-2 and R A- 1-3 is H, and the other is a mixture of one or Multiple R A-1-1-1 substituted C 1 -C 4 alkyl groups, and other variables are defined as described in any of the embodiments of the present invention.
  • R A-1-1-2 , R B -1-1-5 and R B- 1-1- 6 is independently H or C1 - C4 alkyl, and other variables are as defined in any of the embodiments of the present invention.
  • R A-1-1-2 , R B -1-1-5 and R B- 1-1- 6 is independently H, and the definitions of other variables are as described in any aspect of the present invention.
  • the C 1 -C 4 alkyl group substituted by one or more R A-1-1-1 is
  • Other variables are defined as described in any aspect of the present invention.
  • the C 1 -C 4 alkyl group substituted by one or more R A-1-1-1 is
  • Other variables are defined as described in any aspect of the present invention.
  • R 4 and R 5 are independently halogen, C 1 -C 4 alkyl, surrounded by one or more R B -1 substituted C 1 -C 4 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkoxy substituted by one or more R B-2 , other variables are defined as any of the present invention described in the scheme.
  • R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C 6 -C 10 Aryl, C 6 -C 10 aryl substituted with one or more R B-1-3 , 3-12-membered heteroaryl, 3-12-membered heteroaryl substituted with one or more R B-1-4 Aryl, C1- C4alkoxy , C1 - C4alkoxy substituted with one or more deuterium, Other variables are defined as described in any aspect of the present invention.
  • R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C 1 -C 4 alkoxy, C 1 -C 2 alkoxy substituted with one or more deuterium, Other variables are defined as described in any aspect of the present invention.
  • R B-1 is hydroxyl, C 1 -C 4 alkoxy, C substituted by one or more deuteriums 1 -C 2 alkoxy, or Other variables are defined as described in any aspect of the present invention.
  • R B-1 is hydroxyl or Other variables are defined as described in any aspect of the present invention.
  • R B-2 is deuterium, cyano, hydroxyl, C 6 -C 10 aryl, by one or more R B-1-3 substituted C 6 -C 10 aryl, 3-12 membered heteroaryl, 3-12 membered heteroaryl substituted with one or more R B-1-4 or C 1 -C 4 Alkoxy, other variables are as defined in any of the embodiments of the present invention.
  • R B-2 is deuterium, cyano, hydroxyl or C 1 -C 4 alkoxy, and the definitions of other variables As described in any aspect of the present invention.
  • R B-1-3 and R B-1-4 are independently cyano or halogen, and the definitions of other variables As described in any aspect of the present invention.
  • the C 6 -C 10 aryl group substituted by one or more R B-1-3 is Other variables are defined as described in any aspect of the present invention.
  • the 3-12-membered heteroaryl group is Other variables are defined as described in any aspect of the present invention. In some embodiments, in the aromatic vinyl compound represented by formula I-0 or I, the 3-12-membered heteroaryl group substituted by one or more R B-1-4 is Other variables are defined as described in any aspect of the present invention.
  • R B-1-1 and R B-1-2 are independently H or by one or more R B -1-1-1 substituted C 1 -C 4 alkyl; alternatively, R B-1-1 , R B-1-2 and the nitrogen atom to which they are attached together form a 5-7 membered by one or more R B-1-1-2 substituted carboheterocycle, other variables are defined as described in any one of the schemes of the present invention.
  • one of R B-1-1 and R B-1-2 is H, and the other is a mixture of one or Multiple R B-1-1-1 substituted C 1 -C 4 alkyl groups; alternatively, R B-1-1 , R B-1-2 and the nitrogen atoms to which they are attached together form a 5-7 membered
  • R B-1-1-2 substituted carboheterocycles, and other variables are as defined in any of the embodiments of the present invention.
  • the C 1 -C 4 alkyl group substituted by one or more R B-1-1-1 is Other variables are defined as described in any aspect of the present invention.
  • the C 1 -C 4 alkyl group substituted by one or more R B-1-1-1 is Other variables are defined as described in any aspect of the present invention.
  • R B-1-1-2 is C 1 -C 4 alkyl, COOR B-1-1-6 or C 1 -C 4 amide group, other variables are defined as described in any one of the schemes of the present invention.
  • R B-1-1-2 is methyl, carboxyl or -CONH 2 , and the definitions of other variables are as in the present invention described in any scheme.
  • the carboheterocycle is Other variables are defined as described in any aspect of the present invention.
  • the carboheterocycle substituted by one or more R B-1-1-2 is Other variables are defined as described in any aspect of the present invention.
  • the carboheterocycle substituted by one or more R B-1-1-2 is Other variables are defined as described in any aspect of the present invention.
  • R 4 is Other variables are defined as described in any aspect of the present invention.
  • R 5 is halogen, C 1 -C 4 alkyl, C substituted by one or more R B-1 1 -C 4 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkoxy substituted by one or more R B-2 ;
  • R B-1 and R B-2 are independently deuterium , hydroxy, cyano, C 1 -C 4 alkoxy, C 1 -C 2 alkoxy substituted with one or more deuterium or
  • Other variables are defined as described in any aspect of the present invention.
  • At least one of R 15 and R 16 is H or deuterium, and the definitions of other variables are as described in any one of the embodiments of the present invention .
  • R 15 is H or deuterium
  • R 16 is H, deuterium or halogen
  • the definitions of other variables are as in any embodiment of the present invention said.
  • R 1 is halogen, C 1 -C 4 alkyl substituted by one or more halogens, and the definitions of other variables are as in this Invention as described in any aspect of the invention.
  • R 15 is deuterium or halogen, and the definitions of other variables are as described in any one of the embodiments of the present invention.
  • R 16 is deuterium or halogen, and the definitions of other variables are as described in any one of the embodiments of the present invention.
  • the aromatic vinyl compound represented by formula I-0 or I is selected from any of the following schemes, scheme 1:
  • R 2 is R 4 and R 5 are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more R B- 1 , C 1 -C 6 alkoxy, or C 1 -C 6 alkoxy or substituted by one or more C 1 -C 6 alkoxy substituted with one R B-2 ;
  • R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C 1 -C 4 alkoxy, replaced by one or more Deuterium substituted C 1 -C 2 alkoxy or R 3 , R 6 , R 12 , R 13 and R 14 are H;
  • R 2 is halogen, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by one or more R A-1 ;
  • R A-1 is halogen;
  • R 4 is R 5 is halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more R B-1 , C 1 -C 6 alkoxy, or C 1 -C 6 alkoxy or substituted with one or more R B -2 substituted C 1 -C 6 alkoxy;
  • R B-1 and R B-2 are independently deuterium, hydroxy, cyano, C 1 -C 4 alkoxy, substituted with one or more deuterium C 1 -C 2 alkoxy or R 3 , R 6 , R 12 , R 13 and R 14 are H;
  • R 2 is halogen, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by one or more R A-1 ;
  • R A-1 is halogen;
  • R 4 is halogen, C 1 - C 4 alkyl, C 1 -C 4 alkyl substituted with one or more R B-1 , C 1 -C 6 alkoxy or C 1 -C 6 alkane substituted with one or more R B-2 oxy;
  • R B-1 and R B-2 are independently deuterium, hydroxy, cyano, C 1 -C 4 alkoxy, C 1 -C 2 alkoxy substituted with one or more deuterium or
  • R5 is R 3 , R 6 , R 12 , R 13 and R 14 are H;
  • R 2 is R 4 and R 5 are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more R B- 1 , C 1 -C 6 alkoxy, or C 1 -C 6 alkoxy or substituted by one or more C 1 -C 6 alkoxy substituted with one R B-2 ;
  • R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C 1 -C 4 alkoxy, replaced by one or more Deuterium substituted C 1 -C 2 alkoxy or R 3 , R 6 , R 12 , R 13 and R 14 are H; at least one of R 15 and R 16 is H or deuterium;
  • R 2 is halogen, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by one or more R A-1 ;
  • R A-1 is halogen;
  • R 4 is R 5 is halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more R B-1 , C 1 -C 6 alkoxy, or C 1 -C 6 alkoxy or substituted with one or more R B -2 substituted C 1 -C 6 alkoxy;
  • R B-1 and R B-2 are independently deuterium, hydroxy, cyano, C 1 -C 4 alkoxy, substituted with one or more deuterium C 1 -C 2 alkoxy or R 3 ,
  • R 6 , R 12 , R 13 and R 14 are H; at least one of R 15 and R 16 is H or deuterium;
  • R 2 is halogen, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by one or more R A-1 ;
  • R A-1 is halogen;
  • R 4 is halogen, C 1 - C 4 alkyl, C 1 -C 4 alkyl substituted with one or more R B-1 , C 1 -C 6 alkoxy or C 1 -C 6 alkane substituted with one or more R B-2 oxy;
  • R B-1 and R B-2 are independently deuterium, hydroxy, cyano, C 1 -C 4 alkoxy, C 1 -C 2 alkoxy substituted with one or more deuterium or
  • R5 is R 3 , R 6 , R 12 , R 13 and R 14 are H; at least one of R 15 and R 16 is H or deuterium.
  • R 1 is cyano, CH 3 , CD 3 , Cl, CH 2 F, C substituted by one or more halogens 1 - C4 alkyl, other variables are as defined in any of the embodiments of the present invention.
  • R 15 and R 16 are independently H, deuterium, Br or F, and the definitions of other variables are as in any embodiment of the present invention said.
  • the vinyl aromatic compound represented by formula I-0 or I is any of the following compounds:
  • the present invention also provides a method for preparing the vinyl aromatic compound represented by the formula I-0, and the method for preparing the vinyl aromatic compound represented by the formula I-0 includes the following methods 1 and 2 , Method 3, Method 4, Method 5, or Method 6:
  • Method 1 includes the following steps: in a solvent, under the action of a reducing agent, the compound shown in formula II-a-0 and the compound shown in formula III-a are subjected to the following reductive amination reaction to obtain formula I
  • the aromatic vinyl compound shown by -0 can be;
  • R4 is R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R B-1- 1 and RB -1-2 are as defined above;
  • Method 2 includes the following steps: in a solvent, under the action of a base, the compound shown in formula II-b-0 and the compound shown in formula III-a are subjected to the substitution reaction shown below to obtain the compound shown in formula I-
  • the aromatic vinyl compound shown by 0 can be;
  • R4 is R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R B-1- 1 and R B-1-2 are as defined above, X 1 is halogen;
  • Method 3 includes the following steps: in a solvent, under the action of a reducing agent, the compound shown in formula II-c-0 and the compound shown in formula III-a are subjected to the reductive amination reaction shown below, to obtain the compound shown in formula I
  • the aromatic vinyl compound shown by -0 can be;
  • R5 is R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R B-1- 1 and RB -1-2 are as defined above;
  • Method 4 includes the following steps: in a solvent, under the action of a base, the compound shown in formula II-d-0 and the compound shown in formula III-a are subjected to the substitution reaction shown below to obtain the compound shown in formula I-
  • the aromatic vinyl compound shown by 0 can be;
  • R5 is R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R B-1- 1 and R B-1-2 are as defined above, X 2 is halogen;
  • Method 5 includes the following steps: in a solvent, under the action of a reducing agent, the compound shown in formula II-e-0 and the compound shown in formula III-b are subjected to the following reductive amination reaction to obtain formula I
  • the aromatic vinyl compound shown by -0 can be;
  • R2 is R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R A-1- 1 and RA -1-2 are as defined above;
  • Method 6 includes the following steps: in a solvent, under the action of a base, the compound shown in formula II-f-0 and the compound shown in formula III-b are subjected to the substitution reaction shown below to obtain the compound shown in formula I-
  • the aromatic vinyl compound shown by 0 can be;
  • R2 is R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R A-1- 1 and R A-1-2 are as defined above, and X 3 is halogen.
  • the present invention also provides a method for preparing the vinyl aromatic compound shown in formula I, and the preparation method for the vinyl aromatic compound shown in formula I includes the following method one, method two, method three, Method 4, Method 5 or Method 6:
  • the first method includes the following steps: in a solvent, under the action of a reducing agent, the compound shown in formula II-a and the compound shown in formula III-a are subjected to the reductive amination reaction shown below to obtain the reaction shown in formula I
  • the aromatic vinyl compounds can be;
  • R 4 is R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R B-1-1 and R B-1 -2 is defined as before;
  • the second method includes the following steps: in a solvent, under the action of a base, the compound shown in formula II-b and the compound shown in formula III-a are subjected to the substitution reaction shown below to obtain the compound shown in formula I
  • Aromatic vinyl compounds can be;
  • R 4 is R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R B-1-1 and R B-1 -2 is as defined above, X 1 is halogen;
  • Method 3 includes the following steps: in a solvent, under the action of a reducing agent, the compound shown in formula II-c and the compound shown in formula III-a are subjected to the reductive amination reaction shown below to obtain the reaction shown in formula I
  • the aromatic vinyl compounds can be;
  • R 5 is R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R B-1-1 and R B-1 -2 is defined as before;
  • Method 4 includes the following steps: in a solvent, under the action of a base, the compound shown in formula II-d and the compound shown in formula III-a are subjected to the substitution reaction shown below to obtain the compound shown in formula I
  • Aromatic vinyl compounds can be;
  • R 5 is R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R B-1-1 and R B-1 -2 is as defined above, X 2 is halogen;
  • Method 5 includes the following steps: in a solvent, under the action of a reducing agent, the compound shown in formula II-e and the compound shown in formula III-b are subjected to the following reductive amination reaction, as shown in formula I.
  • the aromatic vinyl compounds can be;
  • R 2 is R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R A-1-1 and R A-1 -2 is defined as before;
  • Method 6 includes the following steps: in a solvent, under the action of a base, the compound shown in formula II-f and the compound shown in formula III-b are subjected to the substitution reaction shown below to obtain the compound shown in formula I
  • Aromatic vinyl compounds can be;
  • R 2 is R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R A-1-1 and R A-1 -2 is as defined above, and X3 is halogen.
  • method 1 method 3, method 5, method 1, method 3 or method 5
  • the methods and conditions of the reductive amination reaction may be conventional methods and conditions for such reactions in the art.
  • method 2 method 4, method 6, method 2, method 4 or method 6, the methods and conditions for the substitution reaction may be conventional methods and conditions for such reactions in the art.
  • the present invention also provides a compound represented by II-a-0, II-b-0, II-c-0, II-d-0, II-e-0 or II-f-0,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are as previously defined, X 1 , X 2 and X 3 are independently halogen.
  • the present invention also provides a compound represented by II-a, II-b, II-c, II-d, II-e or II-f,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are defined as follows As previously mentioned, X 1 , X 2 and X 3 are independently halogen.
  • the compound represented by II-a-0 or II-a is any of the following compounds:
  • the compound shown in II-b is the following compound:
  • the compound shown in II-c is any of the following compounds:
  • the compound shown in II-e is any of the following compounds:
  • the present invention also provides any of the following vinyl aromatic compounds, tautomers, stereoisomers, racemates or isotopic derivatives thereof, or them (referring to any of the following vinyl aromatic compounds, pharmaceutically acceptable salts of its tautomers, its stereoisomers, its racemates or its isotopic derivatives);
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned vinyl aromatic compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives, or their ( Refers to the pharmaceutically acceptable salts of the aforementioned aromatic vinyl compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives), and pharmaceutical excipients.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned vinyl aromatic compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives, or their ( Refers to the pharmaceutically acceptable salts of the aforementioned vinyl aromatic compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives), and at least one other drug, wherein said other
  • the drugs are chemotherapy drugs or targeted drugs.
  • the targeted drug is preferably one or more of COX-2 inhibitors, DPP4 inhibitors, CSF-1 ⁇ inhibitors and A2a antagonists.
  • the aromatic vinyl compound, its tautomer, its stereoisomer, its racemate or its isotopic derivative, or them referring to the aforementioned aromatic vinyl compound,
  • the amount of pharmaceutically acceptable salts thereof, tautomers, stereoisomers, racemates or isotopic derivatives thereof can be a therapeutically effective amount.
  • the pharmaceutical excipients can be those widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to enable the subject to dissolve the active ingredient at a desired rate after administration, or to promote the activity of the subject after the composition is administered. The ingredients are effectively absorbed.
  • the pharmaceutical excipients can be inert fillers, or provide some function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
  • Described pharmaceutical adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeteners.
  • adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeten
  • compositions of the present invention can be prepared in light of the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping or lyophilizing processes.
  • compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ophthalmic, rectal, topical or parenteral (infusion, injection, implant Intradermal, subcutaneous, intravenous, intraarterial, intramuscular) administration.
  • the pharmaceutical compositions of the present invention may also be in controlled release or delayed release dosage forms (eg, liposomes or microspheres).
  • solid oral formulations include, but are not limited to, powders, capsules, caplets, softgels, and tablets.
  • liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
  • topical formulations include, but are not limited to, creams, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations.
  • formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection.
  • suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges agent.
  • the present invention also provides the above-mentioned vinyl aromatic compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives, or them (referring to the aforementioned vinyl aromatic compounds, their tautomers) Pharmacologically acceptable salts of their isomers, their stereoisomers, their racemates or their isotopic derivatives), and the use of the above-mentioned pharmaceutical compositions in the preparation of PD-1 inhibitors and/or PD-L1 inhibitors.
  • the PD-1 inhibitor or PD-L1 inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing comparison as a standard sample or a control sample , or made into a kit according to conventional methods in the art to provide rapid detection of PD-1 or PD-L1 inhibitory effect.
  • the present invention also provides the above-mentioned vinyl aromatic compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives, or them (referring to the aforementioned vinyl aromatic compounds, their tautomers) Pharmacologically acceptable salts thereof, their stereoisomers, their racemates or their isotopic derivatives), the above-mentioned pharmaceutical compositions are prepared for prevention and/or treatment and PD-1/PD-L1 signaling pathway The use of medicines related to diseases.
  • the diseases related to the PD-1/PD-L1 signaling pathway are selected from cancer, infectious diseases, autoimmune diseases or their related diseases.
  • the cancer is preferably one or more of lung cancer, esophageal cancer, gastric cancer, colorectal cancer, blood tumor, lymphoma, head and neck cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer.
  • the infectious disease is preferably a bacterial infection and/or a viral infection.
  • the autoimmune disease is preferably one or more of rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, systemic vasculitis and relapsing polychondritis.
  • pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for patient use.
  • patient is preferably a mammal, more preferably a human.
  • salts refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.
  • base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • acids addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a salt is not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • the pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
  • Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluc
  • crystal form means that the ions or molecules in it are arranged strictly periodically in three-dimensional space in a definite manner, and have the regularity of periodic repetition at a certain distance; crystal form, or polymorphism.
  • amorphous means that the ions or molecules are in a disordered distribution state, that is, there is no periodic arrangement between ions and molecules.
  • stereoisomer refers to a cis-trans isomer or an optical isomer. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.).
  • isotopic derivatives refers to "compounds”, “tautomers”, “stereoisomers”, “racemates” and their “pharmaceutically acceptable salts” in which an atom may Available in natural or unnatural abundance.
  • its natural abundance means that about 99.985% of it is protium and about 0.015% is deuterium; its unnatural abundance means that about 95% of it is deuterium. That is, one or more atoms in the terms “compound”, “tautomer”, “stereoisomer”, “racemate” and “pharmaceutically acceptable salts” thereof may be Atoms that exist in unnatural abundances.
  • variable such as R A-1
  • the definition that appears at each position of the variable is independent of the definitions that appear at other positions, and their meanings are independent of each other and do not affect each other.
  • R A-1 the definition of R A-1 and the definition of the remaining positions of R A-1 are independent of each other, and may be different from each other or the same. Additionally, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl refers to a straight or branched chain alkyl group having the indicated number of carbon atoms.
  • alkoxy refers to the group -OR X , wherein R X is an alkyl group as defined above.
  • pharmaceutical excipients refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, and are all substances contained in pharmaceutical preparations other than active ingredients. See the Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • prevention refers to a reduced risk of acquiring or developing a disease or disorder.
  • treatment refers to therapeutic therapy.
  • treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that: the aromatic vinyl compound of the present invention or a pharmaceutically acceptable salt thereof has obvious inhibitory effect on PD-1 and PD-L1, and at the same time has better peak drug concentration, area under the drug-time curve and Oral bioavailability can effectively alleviate or treat cancer and other related diseases.
  • room temperature refers to 10°C-30°C; overnight refers to 8-24 hours, preferably 12-18 hours.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • the nuclear magnetic resonance spectra were obtained by a Bruker Avance-500 instrument. Deuterated dimethyl sulfoxide, deuterated chloroform and deuterated methanol were used as solvents. Silane (TMS) was the internal standard. Mass spectra were obtained with an Agilent Technologies 6110 liquid chromatography-mass spectrometry (LC-MS) instrument using an ESI ion source.
  • the microwave reaction was carried out in the Explorer automatic microwave synthesizer produced by CEM Company in the United States.
  • the frequency of the magnetron was 2450MHz, and the output power of the continuous microwave was 300W.
  • the instrument used for HPLC preparation was Waters 2767, and the preparative column used was XBrige C18, 19 x 150 mm x 5 ⁇ m.
  • Acidic mobile phase 1% formic acid (A) + acetonitrile (B); basic mobile phase: 5 mmol/L ammonium bicarbonate aqueous solution. Flow rate: 15mmL/min. Gradient: 20%-70% (initial mobile phase is 80% water/20% acetonitrile, ending mobile phase is 30% water/70% acetonitrile, where % refers to volume percent).
  • Detection wavelength 214nm and 254nm.
  • Phenylboronic acid (1.626 g, 13.34 mmol) and 2,6-dibromotoluene (5.0 g, 20.0 mmol) were dissolved in a mixed solution of 1,4-dioxane (60 mL) and water (3 mL), and [ 1,1'-Bis(diphenylphosphonium)ferrocene]palladium dichloride (1.154 g, 1.334 mmol) and sodium carbonate (3.535 g, 33.35 mmol). After the reaction system was replaced with nitrogen three times, it was heated to 80°C and stirred for 16 hours.
  • reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (100 mL ⁇ 3) and saturated brine (100 mL) in turn, the obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by Purification by silica gel column chromatography (petroleum ether) gave compound 3-c (1.9 g, yield: 57.2%).
  • reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), then washed with water (50 mL ⁇ 3) and saturated brine (50 mL) successively, the obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by Purification by silica gel column chromatography (petroleum ether) gave compound 3-b (0.89 g, yield: 64.1%).
  • reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (100 mL ⁇ 3) and saturated brine (100 mL).
  • reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (100 mL ⁇ 3) and saturated brine (100 mL).
  • Phenylboronic acid (3.06 g, 10 mmol) and 2-bromo-6-iodobenzonitrile (3.0 g, 12 mmol) were dissolved in a mixed solution of 1,4-dioxane (40 mL) and water (4 mL), and [ 1,1'-Bis(diphenylphosphorus)ferrocene]palladium dichloride dichloromethane complex (731 mg, 1.0 mmol) and sodium carbonate (4.08 g, 30 mmol). After the reaction system was replaced with nitrogen three times, it was heated to 40°C and stirred for 16 hours.
  • reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (100 mL) and saturated brine (100 mL) in this order.
  • 1,4-Dibromo-2,5-dimethylbenzene (2.64 g, 10.0 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), the solution was cooled to -78 °C, under nitrogen environmental protection and stirring, slowly A 2.4M solution of n-butyllithium (5.0 mL, 12.0 mmol) was slowly added dropwise. After the dropwise addition, the temperature of the reaction solution was gradually raised to -20°C. Ten minutes later, it was lowered to -78°C again, and anhydrous N,N'-dimethylformamide (876 mg, 12.0 mmol) was added dropwise.
  • Methylserine (127 mg, 1.06 mmol) was dissolved in methanol (10 mL), and 0.53 M aqueous sodium hydroxide solution (2 mL, 1.06 mmol) was added dropwise with stirring and stirred for 10 minutes.
  • the reaction solution was lowered to 0°C, and a solution of compound 10-a (120.0 mg, 0.35 mmol) in tetrahydrofuran (6 mL) was slowly added dropwise.
  • the reaction solution was warmed to room temperature and stirred for 16 hours.
  • Sodium borohydride (27.0 mg, 0.71 mmol) was added to the reaction solution, and stirring was continued for 2 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was prepared by HPLC to obtain 12 as a white solid (12 mg, yield: 7%).
  • Methyl (S)-1-Boc-piperazine-2-carboxylate 200 mg, 0.819 mmol was dissolved in methanol solution (20 mL), 37% aqueous formaldehyde solution (0.5 mL, 4.10 mmol), glacial acetic acid (99 mg) was added. , 1.64 mmol) and 10% Pd-C (50 mg). The reaction solution was stirred at room temperature for 16 hours under hydrogen.

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Abstract

La présente invention concerne un composé d'éthylène aromatique et son procédé de préparation, un intermédiaire, une composition pharmaceutique et une utilisation associés. Le composé d'éthylène aromatique est représenté par la formule I-0. Le composé d'éthylène aromatique a un effet inhibiteur significatif sur PD-1/PD-L1, a une concentration de pic de médicament plus élevée, une zone plus grande sous la courbe de temps de concentration de médicament, une meilleure biodisponibilité orale, est un type d'inhibiteur à petite molécule extrêmement efficace pour PD-1/PD-L1, et peut soulager de manière efficace ou traiter le cancer et une maladie associée.
PCT/CN2021/117066 2020-09-09 2021-09-08 Composé d'éthylène aromatique et son procédé de préparation, intermédiaire, composition pharmaceutique et utilisation associés Ceased WO2022052926A1 (fr)

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JP2023515809A JP2023540612A (ja) 2020-09-09 2021-09-08 芳香族エチレン系化合物、その製造方法、中間体、医薬組成物及びその使用
US18/042,599 US20230331675A1 (en) 2020-09-09 2021-09-08 Aromatic ethylene compound and preparation method therefor, and intermediate, pharmaceutical composition, and application thereof
EP21865980.3A EP4212511A4 (fr) 2020-09-09 2021-09-08 Composé d'éthylène aromatique et son procédé de préparation, intermédiaire, composition pharmaceutique et utilisation associés

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